Phase I trial of fludarabine, bortezomib and rituximab for relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma.

Author(s): Barr PM, Fu P, Lazarus HM, Horvath N, Gerson SL, Koc ON, Bahlis NJ, Snell MR, Dowlati A, Cooper BW

Affiliation(s): Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA. paul.barr@case.edu

Publication date & source: 2009-10, Br J Haematol., 147(1):89-96. Epub 2009 Jun 29.

Publication type: Research Support, N.I.H., Extramural

Based on the hypothesis that bortezomib may potentiate fludarabine activity by inhibiting DNA repair, we designed a phase I trial using this combination with rituximab in patients with relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma. Twenty-four patients were enrolled. Non-Hodgkin lymphoma subtypes included 12 patients with follicular lymphoma, four with marginal zone lymphoma, three with lymphoplasmacytic lymphoma, three with mantle cell lymphoma and two with small lymphocytic/chronic lymphocytic leukaemia. Fludarabine and bortezomib were escalated in cohorts of three patients. Rituximab was added to the maximum tolerated dose of fludarabine and bortezomib and added significant dose-limiting myelosuppression. The maximum tolerated dose was fludarabine 25 mg/m(2) on days 1-3, bortezomib 1.3 mg/m(2) on days 1, 4, 8, 11, with rituximab 375 mg/m(2) on day 1 administered every 21 d. Clinical responses were observed in 11 patients, five of whom were refractory to their most recent treatment regimen. Six additional patients had stable disease for a median of 10 months (range 4-30+). Cumulative myelosuppression and neuropathy was observed. The combination of fludarabine, bortezomib, and rituximab appears to be an active regimen with manageable toxicity for relapsed NHL.